2. Academic Validation
  3. Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor

  • Nat Commun. 2019 May 24;10(1):2297. doi: 10.1038/s41467-019-09915-2.
Jemima Ho 1,  Xuexin Yang 2,  Spyridoula-Angeliki Nikou 2 3,  Nessim Kichik 2 4,  Andrew Donkin 2,  Nicole O Ponde 2,  Jonathan P Richardson 2,  Remi L Gratacap 5 6,  Linda S Archambault 5,  Christian P Zwirner 5,  Celia Murciano 2 7,  Rhonda Henley-Smith 8,  Selvam Thavaraj 8,  Christopher J Tynan 9,  Sarah L Gaffen 10,  Bernhard Hube 11 12,  Robert T Wheeler 5 13,  David L Moyes 2,  Julian R Naglik 14
Affiliations

Affiliations

  • 1 Centre for Host-Microbiome Interactions, Faculty of Dental, Oral and Craniofacial Sciences, King's College London, London, SE1 1UL, UK. jemima.ho@kcl.ac.uk.
  • 2 Centre for Host-Microbiome Interactions, Faculty of Dental, Oral and Craniofacial Sciences, King's College London, London, SE1 1UL, UK.
  • 3 Protein Phosphorylation Lab, The Francis Crick Institute, London, NW1 1AT, UK.
  • 4 Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
  • 5 Department of Molecular & Biomedical Science, University of Maine, Orono, ME, 04469, USA.
  • 6 Roslin Institute, University of Edinburgh, Edinburgh, EH25 9PS, UK.
  • 7 Postharvest Technology Department, Productos Citrosol, 46721, Potries, Valencia, Spain.
  • 8 Centre for Oral, Clinical & Translational Science, Faculty of Dental, Oral and Craniofacial Sciences, King's College London, London, SE1 1UL, UK.
  • 9 Central Laser Facility, Science and Technology Facilities Council, Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, OX11 0QX, UK.
  • 10 Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
  • 11 Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, 07745, Germany.
  • 12 Friedrich Schiller University, Jena, 07745, Germany.
  • 13 Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, 04469, USA.
  • 14 Centre for Host-Microbiome Interactions, Faculty of Dental, Oral and Craniofacial Sciences, King's College London, London, SE1 1UL, UK. julian.naglik@kcl.ac.uk.
PMID: 31127085 DOI: 10.1038/s41467-019-09915-2
Abstract

Candida albicans is a Fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient Fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swimbladder model of Infection. Investigation into the mechanism of EGFR activation revealed the requirement of Matrix Metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.

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